It is known that the antibacterial and pharmacological properties of many naturally produced aminoglycoside antibiotics can be altered by structural modifications. For example, certain chemical modifications in the gentamicin and kanamycin family of aminoglycoside antibiotics provide structures which are less toxic than the parent antibiotic. Further, in the same family series mentioned above, certain modifications alter the antibacterial spectrum advantageously either by increasing the intrinsic activity or increasing activity against resistant strains.
Further, historically, once an aminoglycoside antibiotic has been in clinical use for a period of time, resistant microorganisms develop. In many cases, the resistance is R-factor mediated and is attributed to the ability of the bacteria to enzymatically modify the amino or hydroxyl groups of the aminoglycoside antibiotics. Thus there is also a need for new entities which can be held in reserve to combat strains which have become resistant to treatment by the clinically used antibiotics.
The fortimicins are a relatively new class of aminoglycoside antibiotics. Fortimicin A is disclosed in U.S. Pat. No. 3,976,768 and fortimicin B in U.S. Pat. No. 3,931,400. Chemical modification of the parent fortimicins have been found to either increase the intrinsic activity of fortimicin A and B, reduce the toxicity or provide therapeutic agents which while having about the same activity, or perhaps somewhat weaker activity but are nevertheless useful as reserve antibiotics in the event resistant strains develop after a period of clinical use of one or more of the fortimicins. The 4-N-acyl derivatives of fortimicin B are disclosed in U.S. Pat. No. 4,091,032 as are the 4-N-alkylfortimicin B derivatives. The 3-O-demethylfortimicin A, fortimicin B and derivatives are disclosed in U.S. Pat. No. 4,124,756. A complete list of the fortimicin patents and pending applications is recited in the accompanying prior art statement filed herewith.
While a number of fortimicin derivatives have been made to date, and valuable therapeutic agents have been identified, the search continues for new fortimicin antibiotics which either have a broader spectrum, less ototoxicity, exhibit oral activity, etc. as well as for agents which can be held in reserve and used to treat infections caused by organisms which become resistant to fortimicin therapy. The present invention provides one such class of compounds, the 1-epi-derivatives of fortimicin A, fortimicin B and fortimicin A and B derivatives.